Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via β1-adrenoceptor activation in the crystalloid perfused normal rabbit heart

James Winter, Kieran E Brack, John H Coote, G André Ng

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8 Citations (Scopus)
133 Downloads (Pure)

Abstract

BACKGROUND/OBJECTIVES: Cardiac contractility modulation (CCM) is a new treatment being developed for heart failure (HF) involving application of electrical current during the absolute refractory period. We have previously shown that CCM increases ventricular force through β1-adrenoceptor activation in the whole heart, a potential pro-arrhythmic mechanism. This study aimed to investigate the effect of CCM on ventricular fibrillation susceptibility.

METHODS: Experiments were conducted in isolated New Zealand white rabbit hearts (2.0-2.5 kg, n=25). The effects of CCM (± 20 mA, 10 ms phase duration) on the left ventricular basal and apical monophasic action potential duration (MAPD) were assessed during constant pacing (200 bpm). Ventricular fibrillation threshold (VFT) was defined as the minimum current required to induce sustained VF with rapid pacing (30 × 30 ms). Protocols were repeated during perfusion of the β1-adrenoceptor antagonist metoprolol (1.8 μM). In separate hearts, the dynamic and spatial electrophysiological effects of CCM were assessed using optical mapping with di-4-ANEPPS.

RESULTS: CCM significantly shortened MAPD close to the stimulation site (Basal: 102 ± 5 [CCM] vs. 131 ± 6 [Control] ms, P<0.001). VFT was reduced during CCM (2.6 ± 0.6 [CCM] vs. 6.1 ± 0.8 [Control] mA, P<0.01) and was correlated (r(2)=0.40, P<0.01) with increased MAPD dispersion (26 ± 4 [CCM] vs. 5 ± 1 [Control] ms, P<0.01) (n=8). Optical mapping revealed greater spread of CCM induced MAPD shortening during basal vs. apical stimulation. CCM effects were abolished by metoprolol and exogenous acetylcholine. No evidence for direct electrotonic modulation of APD was found, with APD adaptation occurring secondary to adrenergic stimulation.

CONCLUSIONS: CCM decreases VFT in a manner associated with increased MAPD dispersion in the crystalloid perfused normal rabbit heart.

Original languageEnglish
Pages (from-to)144-154
Number of pages11
JournalInternational Journal of Cardiology
Volume172
Issue number1
Early online date8 Jan 2014
DOIs
Publication statusPublished - 1 Mar 2014

Keywords

  • Acetylcholine
  • Action Potentials
  • Adrenergic beta-1 Receptor Antagonists
  • Animals
  • Autonomic Nervous System
  • Cardiac Pacing, Artificial
  • Cholinergic Agonists
  • Electrophysiologic Techniques, Cardiac
  • Ganglia, Autonomic
  • Heart
  • Male
  • Metoprolol
  • Myocardial Contraction
  • Perfusion
  • Potassium Compounds
  • Rabbits
  • Receptors, Adrenergic, beta-1
  • Ventricular Fibrillation
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Cardiac contractility modulation
  • Non-excitatory stimulation (NES)
  • Ventricular arrhythmia
  • Action potential duration dispersion

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